Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models

Abstract

Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called consensus molecular subtypes (CMS1-4), each of which has a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed. This study was designed to determine the heterogeneity and identify the presence of CMSs in a large panel of CRC cell lines, primary cultures and patient-derived xenografts (PDX). We provide a repository encompassing this heterogeneity and moreover describe that a large part of the models can be robustly assigned to one of the four CMSs, independent of the stromal contribution. We subsequently validate our CMS stratification by functional analysis which for instance shows mesenchymal enrichment in CMS4 and metabolic dysregulation in CMS3. Finally, we observe a clear difference in sensitivity to chemotherapy-induced apoptosis, specifically between CMS2 and CMS4. This relates to the in vivo efficacy of chemotherapy, which delays outgrowth of CMS2, but not CMS4 xenografts. Combined our data indicate that molecular subtypes are faithfully modelled in CRC cell cultures and PDXs, representing tumour cell intrinsic and stable features. This repository provides researchers with a platform to study CRC using the existing heterogeneity.

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

“…not attributable to infiltrating immune or stroma cells. In further support of this, paired pCRCs and PDXs showed consistent expression levels; 3 out of 15 primary tumors and their paired xenografts showed highly elevated MIR31HG expression (Supporting Information: Fig. S3).…”

Human RECQL4 represses the RAD52‐mediated single‐strand annealing pathway after ionizing radiation or cisplatin treatment

“…However, a recent study revealed that most xenograft models maintain the original subtype. 51 Consistently, the CGH results showed that HCT116 cells exhibited minimal genomic changes upon multiple passages (Fig. S9).…”

Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch

“…[12,13] These cell lines represent ad iverses et of tumors, spanningt he four subtypes of CRC andb oth MMR-and MMR + phenotypes. [14,15] The toxicities of RhPPO,w hich selectively targets MMR deficiencies,a nd the non-selectiveF DA-approved chemotherapeutic cisplatin, which covalently binds the abundant d(GpG) motifs present in all DNA (Figure 1), were assessed in this cell line panel using al uciferase-based luminescence assay which measures ATPf rom living cells. Dose-responsec urves and corresponding IC50 values (50 %i nhibitory concentration) were determined for each therapeutic and are shown in Figure 2 and Table S2 (Supporting Information).…”